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Published on: January 30, 2014
Microglial Activation Mediates Drp1-Dependent Mitochondrial Fission and Neuronal Apoptosis in a
Meng-Jie Chen1, Jia-Qi Ning1, Jia-Xi Liu1
1Department of Anesthesiology, Beijing Hospital of traditional Chinese medicine, Capital Medical University, Beijing, 100010, China.
Abstract:
Neuroimmune dysregulation, characterized by microglial overactivation and imbalances in mitochondrial dynamics within the central nervous system represents a core pathological mechanism in postoperative cognitive dysfunction (POCD). This study investigated the neuroinflammation-mitochondrial interaction through the establishment of in vivo and in vitro models using lipopolysaccharide (LPS). Findings indicated that LPS-induced microglial overactivation was associated with marked upregulation of mitochondrial fission proteins, including phosphorylated Drp1 at Ser616, mitochondrial Drp1, and Fis1, along with downregulation of mitofusin-2. These alterations promoted mitochondrial fragmentation in hippocampal neurons, which subsequently led to mitochondrial membrane potential depolarization, adenosine triphosphate depletion, and excessive production of reactive oxygen species. This cascade further activated the intrinsic apoptotic pathway via Bax/Bcl-2 imbalance and caspase-9/3 activation. Conversely, administration of the Drp1 inhibitor Mdivi-1 reduced microglial activation, attenuated inflammatory cytokine levels, restored mitochondrial network integrity and function, inhibited neuronal apoptosis, and ameliorated LPS-induced spatial memory impairment in behavioral assays. These findings indicate that microglial activation-induced mitochondrial fission plays a pivotal role in inflammation-related cognitive impairment. Moreover, they highlight mitochondrial fission as a promising therapeutic target for intervention in POCD.
Insights
Microglial overactivation drives mitochondrial fission, impairing cognitive function in postoperative cognitive dysfunction (POCD). Targeting mitochondrial fission offers a promising therapeutic strategy for POCD.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Neuroinflammation and mitochondrial dysfunction are key in postoperative cognitive dysfunction (POCD).
- Microglial overactivation and altered mitochondrial dynamics are implicated in central nervous system pathology.
Purpose of the Study:
- To investigate the link between neuroinflammation and mitochondrial dynamics in POCD.
- To explore the role of microglial activation in mitochondrial fission and subsequent neuronal damage.
Main Methods:
- Established in vivo and in vitro models using lipopolysaccharide (LPS) to induce neuroinflammation.
- Analyzed mitochondrial fission/fusion protein expression (Drp1, Fis1, mitofusin-2) and mitochondrial function.
- Assessed neuronal apoptosis, spatial memory, and the effects of the Drp1 inhibitor Mdivi-1.
Main Results:
- LPS-induced microglial activation upregulated fission proteins (p-Drp1, Drp1, Fis1) and downregulated fusion protein (mitofusin-2).
- This led to mitochondrial fragmentation, membrane depolarization, ATP depletion, ROS production, and apoptosis in hippocampal neurons.
- Mdivi-1 treatment reversed these effects, reducing inflammation, apoptosis, and improving spatial memory.
Conclusions:
- Microglial activation-induced mitochondrial fission is a critical factor in inflammation-related cognitive impairment.
- Mitochondrial fission represents a potential therapeutic target for preventing and treating POCD.
